Background & Aims
Chronic neuropathic pain (NP) imposes a large burden for individuals with spinal cord injuries (SCI), affecting approximately 53% of all patients.1 The pathophysiological mechanisms of NP are poorly understood,2 with central sensitization along the nociceptive neuraxis being a potential key mechanism.3 In that regard, objective surrogate measures to assess such sensitized states are warranted and so far, reduced habituation to noxious stimuli applied above the SCI was demonstrated to be linked to central sensitization in individuals with SCI either by using evoked potentials4 or autonomic measures5 as readouts. However, to disentangle the primary origin of sensitization (spinal or supraspinal), multiple testing sites are required.3 Therefore, the aim of this study was to unravel whether central sensitization is more driven by spinal or supraspinal processes, examining the most painful area below and a control area above the level of SCI, respectively.
Methods
The evaluation of habituation to repetitive, noxious heat stimulation was conducted in 16 individuals with NP after SCI and 15 age- and gender-matched healthy controls (HC). Subjective pain ratings, contact heat evoked potentials (CHEP) and heat-induced sympathetic skin responses (SSR) were used as readouts to assess habituation. Habituation indices (in %) were calculated between the two consecutive blocks of stimulation, consisting of 15 phasic heat stimuli (42-52°C) for each tested area, namely the most painful (below SCI) and the control area (above SCI). These indices were then correlated to clinical pain characteristics, such as pain extent and intensity, as assessed through quantitative pain drawings. A particular within-block habituation analysis (first to the last CHEP) was performed for CHEPs in order to extend on a previous investigation revealing diminished habituation in an SCI cohort with NP compared to an SCI cohort without NP and healthy controls.4
Results
Both the SCI cohort and HC displayed significant habituation across all three readouts in both areas (all p<0.05, pain ratings; control-SCI: -24%, painful-HC: -24%, control-HC: -14%, CHEP; painful-SCI: -14%, control-SCI: -19%, painful-HC: -27%, control-HC: -33%, SSR; painful-SCI: -33%, control-SCI: -52%, painful-HC: -53%, control-HC: -50%) except for pain ratings in the SCI group in the painful area (painful-SCI: -18%, p=0.08). Overall, no group differences were found in either area or readout (all p>0.05). However, individuals with a high NP extent showed lower SSR habituation in the control area (r=0.55, p=0.03). Moreover, individuals with SCI ON (n=8) pain medication showed more SSR habituation than the individuals OFF pain medication (n=8, p=0.03). The within-block analysis of CHEPs from the control area revealed significant habituation in HC (-27%, p<0.001), but no significant habituation in the SCI cohort (+3%, p=0.30). Overall, no group differences were detected (p=0.22).
Conclusions
Our study suggests that neuropathic pain following SCI might be primarily driven by supraspinal sensitization. Individuals with SCI experiencing more widespread NP exhibited increased signs of central sensitization, as evidenced by reduced SSR habituation in the control area. Furthermore, pain medication seems to normalize SSR habituation, emphasising a systemic medication effect. Additionally, the within-block analysis of CHEPs habituation demonstrates significant habituation only in HC. Despite the absence of group differences, our results align with previous studies involving individuals with SCI,4 showing a lack of habituation when tested above the level of SCI. Importantly, a potential involvement of spinal sensitization processes can be inferred from the absence of pain rating habituation within the painful area below the SCI. Our findings highlight the potential for targeted treatments specifically addressing supraspinal sensitization processes.
References
1.Burke D, Fullen BM, Stokes D, Lennon O. Neuropathic pain prevalence following spinal cord injury: A systematic review and meta-analysis. European Journal of Pain (United Kingdom). 2017;21(1):29-44. doi:10.1002/ejp.905
2.Eide PK. Pathophysiological Mechanisms of Central Neuropathic Pain after Spinal Cord Injury. Vol 36.; 1998. https://www.stockton-press.co.uk/sc
3.Arendt-Nielsen L, Morlion B, Perrot S, et al. Assessment and manifestation of central sensitisation across different chronic pain conditions. European Journal of Pain (United Kingdom). 2018;22(2):216-241. doi:10.1002/ejp.1140
4.Kumru H, Soler D, Vidal J, Tormos JM, Pascual-Leone A, Valls-Sole J. Evoked potentials and quantitative thermal testing in spinal cord injury patients with chronic neuropathic pain. Clinical Neurophysiology. 2012;123(3):598-604. doi:10.1016/j.clinph.2011.07.038
5.Lütolf R, Rosner J, Curt A, Hubli M. Indicators of central sensitization in chronic neuropathic pain after spinal cord injury. European Journal of Pain (United Kingdom). 2022;26(10):2162-2175. doi:10.1002/ejp.2028
6.Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain. 2003;103(3):249-257. doi:10.1016/S0304-3959(02)00452-9
7.Finnerup NB, Jensen TS. Spinal cord injury pain – Mechanisms and treatment. Eur J Neurol. 2004;11(2):73-82. doi:10.1046/j.1351-5101.2003.00725.x
8.Moisset X, De Andrade DC, Bouhassira D. From pulses to pain relief: An update on the mechanisms of rTMS-induced analgesic effects. European Journal of Pain (United Kingdom). 2016;20(5):689-700. doi:10.1002/ejp.811
9.Austin PD, Siddall PJ. Virtual reality for the treatment of neuropathic pain in people with spinal cord injuries: A scoping review. Journal of Spinal Cord Medicine. 2021;44(1):8-18. doi:10.1080/10790268.2019.1575554
Presenting Author
Joëlle Katharina Metzger
Poster Authors
Joëlle Metzger
MSc
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich
Lead Author
Robin Lütolf
PhD
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich
Lead Author
Iara De Schoenmacker
PhD
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich
Lead Author
Sarah Mehli
MSc
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich
Lead Author
Jan Rosner
MD
Danish Pain Research Center, Aarhus University
Lead Author
Armin Curt
MD
Spinal Cord Injury Center, Balgrist University Hospital, University of Zurich
Lead Author
Michèle Hubli
Spinal Cord Injury Research Center
Lead Author
Topics
- Assessment and Diagnosis